tbuckley/cabot-search huggingface dataset:
Phase I study combining pembrolizumab and aromatase inhibitor in patients with metastatic hormone receptor–positive breast cancer.
Authors: Xuan Ge, Susan Elaine Yost, Jin Sun Lee, Paul Henry Frankel, Christopher Ruel, Yujie Cui, Mireya Murga, Aileen Tang, Norma Martinez, Samuel Chung, Christina Haeyoung Yeon, Daphne B. Stewart, Daneng Li, Swapnil Padmakar Rajurkar, George Somlo, Joanne E. Mortimer, James Ross Waisman, Yuan Yuan
Journal: Journal of Clinical Oncology (2022)

1053 Background: Aromatase inhibitor (AI) is standard of care for patients with hormone receptor positive (HR + ) human epidermal growth factor receptor 2-negative (HER2 - ) metastatic breast cancer (MBC). The current phase I trial was designed to test the safety and efficacy of AI and the immune checkpoint inhibitor pembrolizumab (NCT 02648477). Methods: Key eligibility criteria were HR + HER2 - MBC per ASCO/CAP; RECIST 1.1 measurable disease; adequate organ function; and ECOG 0-1. Eligible patients received 200 mg pembrolizumab IV every 3 weeks plus AI until progression or unacceptable toxicity. Primary objectives were to evaluate the safety and efficacy of this combination. This study employed a 3-at-risk design with a lead-in at the standard dosing of both AI and pembrolizumab with a targeted accrual of 20 patients. Results: A total of 20 patients were accrued between March 2016 and April 2017. Median age was 62 (range 34-79), with 75% white, 15% Asian and 10% unknown. Median lines of therapy were 3 (0, 9). All but one patient received aromatase inhibitor and/or fulvestrant prior to enrollment. The combination was well tolerated, and the most common adverse events were grade 2 fatigue (35%), rash (15%), and hot flashes (10%). Grade 3 adverse events were elevated AST/ALT (5%), rash (5%), and lymphopenia (5%). Responses were 10% partial response and 15% stable disease, resulting in a clinical benefit rate (CBR) of 20% at 6 months. Median follow-up time was 40.1 months (range 31.3 – 46.8 months). Median progression free survival was 1.8 months (95% CI 1.6, 2.6) and median overall survival was 17.2 months (95% CI 9.4, NA). 14 tumor specimens had programmed death ligand 1–positive (PD-L1) by 22C3 testing, including 3 PD-L1-positive and 11 PD-L1 negative. No association between PD-L1 and response was found. Conclusions: The combination of pembrolizumab and AI is well tolerated in patients with HR + HER2 - MBC who were not pre-selected for PD-L1. There was minimal overall clinical activity observed beyond what was to be expected with AI alone in this group of patients. Clinical trial information: NCT 02648477.
The Efficacy of <scp>Short‐Term</scp> Bridging Strategies With High‐ and <scp>Low‐Dose</scp> Prednisolone on Radiographic and Clinical Outcomes in Active Early Rheumatoid Arthritis: A <scp>Double‐Blind</scp>, Randomized, <scp>Placebo‐Controlled</scp> Trial
Authors: Dietmar Krause, Anna Mai, Renate Klaassen‐Mielke, Nina Timmesfeld, Ulrike Trampisch, Henrik Rudolf, Xenofon Baraliakos, Elmar Schmitz, Claas Fendler, Claudia Klink, Stephanie Boeddeker, Ertan Saracbasi‐Zender, Hans‐Joachim Christoph, Manfred Igelmann, Hans‐Juergen Menne, Albert Schmid, Rolf Rau, Siegfried Wassenberg, Nilüfer Sonuc, Claudia Ose, Carmen Schade‐Brittinger, Hans J. Trampisch, Juergen Braun
Journal: Arthritis & Rheumatology (2022)

In active early rheumatoid arthritis (RA), glucocorticoids are often used for bridging, due to the delayed action of methotrexate. This study was undertaken to compare the effect of 3 bridging strategies, including high-dose and low-dose prednisolone, on radiographic and clinical outcomes.Adult RA patients from 1 rheumatology hospital and 23 rheumatology practices who presented with moderate/high disease activity were randomized (1:1:1) to receive 60 mg prednisolone (high-dose prednisolone [HDP]) or 10 mg prednisolone (low-dose prednisolone [LDP]) daily (tapered to 0 mg within 12 weeks) or placebo. The 12-week intervention period was followed by 40 weeks of therapy at the physicians' discretion. The primary outcome measure was radiographic change at 1 year measured using the total modified Sharp/van der Heijde score (SHS). Disease activity was assessed with the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR).Of 395 randomized patients (HDP, n = 132; LDP, n = 131; placebo, n = 132), 375 (95%) remained in the modified intention-to-treat analysis. Mean ± SD changes in SHS scores in the 3 groups after 1 year were comparable: mean ± SD 1.0 ± 2.0 units in the HDP group, 1.1 ± 2.2 units in the LDP group, and 1.1 ± 1.5 units in the placebo group. The primary analysis showed no superiority of HDP compared to placebo (estimated difference of the mean change -0.04 [95% confidence interval (95% CI) -0.5, 0.4]). At week 12, the mean DAS28-ESR differed: -0.6 (95% CI -1.0, -0.2) for HDP versus placebo; -0.8 (95% CI -1.2, -0.5) for LDP versus placebo. At week 52, there was no significant difference in DAS28-ESR between the 3 groups (range 2.6-2.8). Serious adverse events occurred similarly often.Short-term glucocorticoid bridging therapy at a high dose showed no benefit with regard to progression of radiographic damage at 1 year.
Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine
Authors: Guangting Zeng
Journal: The Lancet Microbe (2022)

To withstand COVID-19 and prepare for future threats, the world needs to produce enough doses of the most effective, adaptable, and rapidly manufacturable vaccines. mRNA vaccines are popular because of quality advantages, such as rapid production and safety. The safety and immunogenicity of the SARS-COV-2 ARCoV mRNA vaccine has also attracted attention. But the vaccine results are hardly encouraging.1Chen G-L Li X-F Dai X-H et al.Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial.Lancet Microbe. 2022; 3: e193-e202Summary Full Text Full Text PDF PubMed Scopus (17) Google Scholar In terms of safety, the proportion of adverse events, such as fever after one dose of vaccine, was quite high compared with the two main mRNA vaccines on the market,2Meo SA Bukhari IA Akram J Meo AS Klonoff DC COVID-19 vaccines: comparison of biological, pharmacological characteristics and adverse effects of Pfizer/BioNTech and Moderna vaccines.Eur Rev Med Pharmacol Sci. 2021; 25: 1663-1669PubMed Google Scholar which might have something to do with the direct use of unmodified RNA molecules to trigger a strong immune response. In addition, the data showed that among the five doses of 5–25 mg, the 15 mg group produced significantly higher levels of neutralising antibodies than the other groups, up to twice the serum level of a panel of patients recovering from COVID-19. But higher and lower concentrations (20 mg vs 10 mg) produced less than half the neutralising antibody levels of the 15 mg group. This suggests that the vaccine has a narrow range of effective doses, making it difficult to lower the dose to reduce adverse effects and reducing its real-world use on a large scale. Because of the heterogeneity of the population, the effective dose will fluctuate, and a certain proportion of people will not be fully protected. Unlike the vaccines by Pfizer–BioNTech and Moderna,2Meo SA Bukhari IA Akram J Meo AS Klonoff DC COVID-19 vaccines: comparison of biological, pharmacological characteristics and adverse effects of Pfizer/BioNTech and Moderna vaccines.Eur Rev Med Pharmacol Sci. 2021; 25: 1663-1669PubMed Google Scholar in which one vaccine requires storage conditions of −70°C and the other needs to be stored at −20°C, ARCoV mRNA vaccines are very stable and can be stored and transported under cold storage conditions, making it easy to vaccinate the public in remote areas with poor infrastructure. However, the safety and immunogenicity of ARCoV mRNA vaccines might require technical optimisation. I declare no competing interests. Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trialARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale. Full-Text PDF Open Access
HPV E7 oncogene expression impairs Rb function and confers CDK4/6 inhibitor resistance in cervical cancer.
Authors: Yudi Xiong, Yuan Wang, Haibin Ou, Yunfeng Zhou
Journal: Journal of Clinical Oncology (2022)

e17504 Background: Malignant tumor proliferation is one of the important factors for poor prognosis. CDK4/6 inhibitors can delay tumor progression by inhibiting cell cycle and inducing apoptosis, so they are potentially effective broad-spectrum anti-tumor targeted drugs, but drug resistance limits their clinical applications. Our previous research found that the CDK4/6 inhibitor LEE011 has anti-tumor effects on cervical cancer C33A cells, but no anti-tumor activity against HeLa. The mechanism is not very clear, we speculate that it is related to HPV infection. In this research, our aim is to clarify the correlation between HPV and tumor drug sensitivity and explore the possible mechanisms. Methods: Two HPV positive human cervical cancer cell lines, SiHa and Caski were chosen to verify the sensitivity to LEE011 by cell morphology, cell cycle and apoptosis. The antitumor activity of CDK4/6 inhibitor LEE011 by E7 knockin C33A and E7 knock-down HeLa cell lines was assessed by in vitro clonogenic assay, flow cytometry, and target inhibition verified by immunoblotting. Effects of LEE011 and E7 knock-down combination in vivo were studied by xenograft tumor regrowth delay, and tissue section immunohistochemistry. Results: SiHa and Caski were insensitive to LEE011 antitumor activity. Enhancement of drugsensitivity was lost in cell lines with HPV positive. After down-regulation of E7, LEE011 treatment increased the inhibition cell proliferation and pro-apoptosis of HeLa. Mechanistically, the loss of E7-induced Rb inactivation and LEE011 inhibited Rb phosphorylation, leading to cell-cycle arrest. In vivo, LEE011 inhibited tumor regrowth, with sustained inhibition of cyclin D-CDK4/6-Rb-E2F1 activity in E7 knock-down HeLa. However, up-regulation of E7 can reduce the ability of LEE011 to inhibit cell proliferation and pro-apoptosis of C33A. In summary, our study signifies inhibiting the CDK4/6 pathway by LEE011 in combination with down-regulation of E7 as a promising therapeutic strategy to treat cervical cancer. Conclusions: These findings suggested that HPV can affect Rb function by expressing oncoprotein E7 leading to resistance to targeted drug therapy, which means that HPV may be a biomarkers of drug therapy efficacy.
Real-world trends of PARPi maintenance treatment uptake and progression-free survival (PFS) in patients (pts) with newly diagnosed advanced ovarian cancer (AOC) in the United States.
Authors: John K Chan, Jinan Liu, Jinlin Song, Cheryl Xiang, Eric Q. Wu, Linda Kalilani, Jean Hurteau, Premal H. Thaker
Journal: Journal of Clinical Oncology (2022)

6580 Background: Since 2018, the FDA has approved 2 PARP inhibitors (PARPi), niraparib and olaparib, for first-line (1L) maintenance therapy for OC. Using real-world population data, we assessed trends of 1L PARPi maintenance treatment uptake and PFS of pts with newly diagnosed AOC. Methods: Pts diagnosed with AOC between January 1, 2017, and June 30, 2021, who completed 1L chemo were identified from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. We calculated descriptive statistics describing pt demographics, clinico-pathological characteristics, and 1L treatment patterns. The use of PARPi or active surveillance (AS) was identified during a 120-day period after the last dose of 1L chemo. The end of the 1L treatment identification period was defined as the index date. Time to next treatment was used as a proxy for PFS and was defined as time from the index date to the next therapy, last clinical activity, end of study period, or death. Kaplan-Meier methods and Cox models were used to analyze the PFS endpoint. Results: A total of 705 pts were included in the study; 166 received PARPi monotherapy (PARPi mono) and 539 underwent AS after completion of 1L chemo. Median age was 68 y for AS vs. 65 y for PARPi mono (Table). Median time from last chemo to initiation of PARPi mono was 48.5 d. Median follow-up was 20.6 mo for AS and 10.9 mo for PARPi mono. In the overall group, median PFS (mPFS) was 9.53 mo for AS vs. not reached (NR) for PARPi mono. In those with BRCA mutations ( BRCAm), corresponding mPFS was 11.4 mo vs. NR and for BRCA wild type ( BRCAwt) was 9.1 mo vs. 13.5 mo. On multivariate analysis, 1L PARPi maintenance was an independent predictor for improved PFS when compared to AS in all pts (HR, 0.47; 95% CI, 0.34-0.63), BRCAm (HR, 0.17; 95% CI, 0.07-0.41) and BRCAwt (HR, 0.50; 95% CI, 0.35-0.72). Stage IV at initial diagnosis, no debulking surgery, residual disease, and BRCAwt status were associated with poorer PFS. Trends analysis over the 4-year study period showed PARPi mono use increased from 6% in 2017 to 53% in 2021. Conclusions: This real-world analysis shows that adoption of PARPi mono in the 1L maintenance setting in pts with newly diagnosed AOC has increased to 53% in 2021. PARPi use, when compared with AS, was associated with significantly improved mPFS in both pts with BRCAm and BRCAwt. [Table: see text]
Activated protein kinase C-alpha as a simple test for urothelial cancer screening.
Authors: Junichi Inokuchi, Masaharu Murata, Takahito Kawano, Jeong-Hun Kang, Fumio Kinoshita, Takashi Matsumoto, Keisuke Monji, Eiji Kashiwagi, Ario Takeuchi, Masaki Shiota, Masatoshi Eto
Journal: Journal of Clinical Oncology (2022)

e16552 Background: The development of a non-invasive, highly predictive diagnostic test for urothelial cancer (UC) would greatly benefit patients. Although numerous urine-based tests have been developed, it is not widely used, except for urine cytology, due to insufficient sensitivity, negative predictive value and high cost. Previously we reported that protein kinase C-alpha (PKCα) is overexpressed or activated in several cancer tissues but not in normal tissue, and we developed an activated PKCα-specific peptide substrate (FKKQGSFAKKK; Patent No. 5476559). The purpose of this study was to investigate the potential for UC screening of simple test detecting activated PKCα. Methods: This institutional review board-approved prospective study included patients with bladder cancer or upper urinary tract UC who underwent surgery at Kyushu University Hospital between September 2018 and December 2020. Patients with benign urologic disorders or healthy volunteers were included as a control group. Patients with prostate cancer (PC) or renal cell carcinoma (RCC) who underwent curative surgery were included as other genitourinary (GU) cancer group. Patients with other coexisting malignant tumors were excluded. Urine samples were collected prior to surgery, 20 mL of urine was centrifuged, and the pellet was lysed for analysis. We evaluated the phosphorylation status of the activated PKCα-specific peptide substrate by MALDI-TOF mass spectrometry. The utility of activated PKCα as a urinary biomarker was evaluated by its sensitivity and negative predictive value when compared to control group or other GU cancers group. Results: Urine samples were obtained from 226 individuals, which included 98 patients with UC, 51 with other GU caners, and 77 with control group. Of the 98 patients with UC, activated PKCα was detected in 75 patients, with sensitivity of 76.5%. The sensitivity in patients with high-grade and low-grade UC were 84% and 62%, respectively. The sensitivity in those with high-grade UC increased to 93% when combined with urine cytology. On the other hand, activated PKCα were rarely detected in non-UC patients which includes other GU cancers group and control group. The specificity among the non-UC patients was 74.2%. In the comparison between patients with UC and non-UC, the negative predictive value of activated PKCα was 80.5%. The area under the receiver operating characteristic curve (AUC) for detecting UC of activated PKCα was 0.80. Conclusions: This study demonstrates the utility of activated PKCα as a novel urine screening test for UC. (Patent Application No. PCT/JP2020/045257) Since this test is based on a single target, inexpensive detection devices can be developed.
Chronic prurigo
Authors: Laurent Misery
Journal: British Journal of Dermatology (2022)

Summary Chronic prurigo is a distinct disease defined by the presence of chronic pruritus for at least 6 weeks, a history and/or signs of repeated scratching, and multiple localized or generalized pruritic skin lesions (whitish or pinkish papules, nodules and/or plaques). Although chronic prurigo is frequently named prurigo nodularis, the nodular type of chronic prurigo is only the main clinical aspect of chronic prurigo. Chronic prurigo occurs due to neural sensitization to pruritus and the development of a vicious pruritus–scratching cycle. Chronic prurigo can be of allergological, dermatological, systemic, neurological, psychiatric/psychosomatic, mixed or undetermined origin. The prevalence is still debated. The burden is high. Current treatments often remained disappointing. Fortunately, recent research results on the pathophysiology of pruritus evidenced neuroimmune interactions and allow new therapeutic perspectives. Among them, antagonists of T-helper 2 cytokines, κ-opioids and Janus kinase inhibitors may be promising. What is already known about this topic? Chronic prurigo or prurigo nodularis is poorly known by dermatologists and the definition was rather vague until recently. What does this study add? This review provides a summary of the recent developments of nosology and research (from basic research to epidemiology and clinical research), and current and near-future management are then discussed.
Evaluating cancer awareness months and cancer screening tests through internet search big data.
Authors: Bernard Tawfik
Journal: Journal of Clinical Oncology (2022)

e24038 Background: Cancer Awareness Months (CAMs) aim to increase public recognition of specific cancers through education and screening promotion, but their effectiveness is uncertain. This study was designed to characterize the relationship between internet search interest (ISI) of breast, colon, lung, and prostate cancers and related screening test terms with their respective CAMs with the goal of better understanding CAM effectiveness across time and geographic scale. Methods: ISI was collected from sampled Google Search data from Google Trends on a national, state, and metropolitan level between 2004 and 2021. The ISI for cancer and cancer screening terms for each respective CAM was compared to ISI for nonadjacent months and across regionality. Results: Breast CAM was associated with increased ISI for both cancer (p &gt; 0.001) and cancer screening (p &gt; 0.001) terms. Colon CAM was associated with higher cancer term ISI (p = 0.004), but had mixed effects on screening ISI across terms. Lung CAM was not associated with a change in cancer term ISI (p = 0.573) and had mixed effects across screening terms. Prostate CAM was not linked to ISI changes for any associated terms. Regional variation in ISI was found in all cases. Conclusions: Given the high accessibility and scalability of Google Trends, this tool can be used to practically evaluate and guide the strategies of CAM campaigns across cancer type and geographic scale. Future directions include broadening the geographic scope and comparatively assessing specific CAM campaign strategies.
Association between state Medicaid policies and accrual of Black participants to cancer clinical trials.
Authors: Samuel U Takvorian, Paula Chatterjee, Ronac Mamtani, Yaxin Wu, Carmen Guerra, Rachel M. Werner, William Schpero
Journal: Journal of Clinical Oncology (2022)

1501 Background: Black individuals remain underrepresented in U.S. cancer clinical trials, partly due to financial barriers to participation. While coverage of the routine costs of trial participation has long been mandatory for Medicare and the commercially insured, only 16 states have enacted similar mandates for Medicaid enrollees. Given the disproportionate representation of Black individuals in state Medicaid programs, we hypothesized that such mandates may have led to improved accrual of Black participants to cancer clinical trials. Methods: We conducted a retrospective, quasi-experimental study using de-identified data from the ECOG-ACRIN Cancer Research Group to evaluate changes in the accrual of Black participants to cancer clinical trials associated with state-mandated Medicaid coverage of routine trial costs. The study population included non-elderly adults enrolled in therapeutic clinical trials for breast, colorectal, lung, or prostate cancer from 2000-2019. We employed a difference-in-differences approach with event-study specification to compare outcomes in states that mandated Medicaid coverage of routine trial costs relative to states that did not, before and after mandates were enacted. Outcomes included the proportion of trial participants who had Medicaid insurance (vs. non-Medicaid) and the proportion who were Black (vs. non-Black). Models adjusted for age, sex, cancer type, cancer stage, study phase, and study site (community vs. academic). Results: Among 24,321 trial participants (mean age 52.0 [SD 8.2] years, 82.8% female), 7.2% had Medicaid coverage and 10.5% were Black. Compared to states without Medicaid coverage mandates, states with mandates had a statistically significant increase in the proportion of Black trial participants in the first year following the mandate (+6.4 percentage points [95%CI 1.8% to 11.0%]) but not in subsequent years. There was no association between state mandates and the proportion of trial participants enrolled in Medicaid (effects ranged from -0.7 percentage points [95%CI -4.6% to 3.3%] in the first year after mandates to -3.9% [95%CI -8.6% to 0.8%] in the third year). Conclusions: State-mandated Medicaid coverage of the routine costs of trial participation was associated with a short-term increase in the proportion of Black trial participants. These findings suggest that Medicaid policies have the potential to improve representation of racial minority groups in cancer clinical trials, and support recent federal legislation mandating state Medicaid programs to cover trial participation costs as of January 2022. Our study was limited by use of data from only one large cancer research group, focus on only four common cancers, and limited power to analyze the policy impact for other racial and ethnic minority groups. Additional work is needed to replicate these findings in larger cohorts of trial participants.